Members of the steroid/thyroid receptor superfamily have been shown to be important for the regulation of target genes essential for cellular differentiation and development. Preliminary results obtained have indicated that the chicken ovalbumin upstream promoter element transcription factors (COUP-TFs), members of the receptor superfamily, down regulate the activities of other members in the gene family, especially, thyroid, vitamin D and retinoic acid receptors. In addition to the negative regulatory activity, COUP-TFs also have the potential to activate target genes. Taken together, they support the idea that COUP-TFs play a primordial role in modulating gene activities in this family and thus directly or indirectly regulating development and differentiation. The long term goal of our laboratory is to define the biological function of these "orphan" receptors. Before, one can reach that goal, one has to dissect the mechanism of COUP-TFs on gene regulation and the interplay between members of the steroid/thyroid hormone receptor superfamily. In this application, we design experiments by using various in vitro methodologies to elucidate the complex regulatory mechanism by COUP-TFs. The results obtained will be complemented by the in vivo studies on the effect of gene activities when COUP-TF gene activities are up- or down-regulated. It is expected that the understanding derived from this project will be relevant to the biology of development and differentiation. The proposed studies should also be pertinent to development of more precise theories for the biochemical mechanism of action of hormone in general and more specifically, thyroid, retinoic acid and vitamin D.